Short arms and lanky legs: the genetic basis of walking on two legs

Amazing stuff! Is bipedalism a result of global warming?

"... The genome-wide map that Narasimhan and his colleagues generated identified 145 genetic locations associated with changes to skeletal proportions. Many of the identified regions are known to have roles in skeletal development and 45 of the locations overlapped a single protein-coding gene. Of those, 32 have previously been identified as resulting in abnormal skeletons when disrupted in mice, and 4 as causing rare skeletal diseases in humans. ...
One theory for why early hominins evolved upright walking is that their bodies were better able to keep cool in hot environments. Using biobank data on metabolic rate and body mass, the researchers found support for this hypothesis: as leg length increases, heat dissipation to stay cool improves. ...
the study identified genetic regions associated with osteoarthritis of the hips and knees ..."

From the editor's summary and abstract:

"Editor’s summary

Many skeletal changes occurred on the path to modern humans, resulting in bipedalism but also susceptibility to musculoskeletal diseases. Kun et al. used imaging data from more than 30,000 UK Biobank participants to characterize skeletal proportions, assessing the genetic basis of these features, as well as their relationships to each other. They found that limb proportions are uncorrelated with body width proportions, that there are associations between hip- and leg-related skeletal proportions and osteoarthritis, and that there is enrichment for loci associated with skeletal proportion in genomic regions associated with human-specific evolution. This study demonstrates the utility of using imaging data from biobanks to understand both disease-related and normal physical variation among humans. ...

Structured Abstract

INTRODUCTION

Humans are the only bipedal great apes, owing to our distinctive skeletal form. Morphological changes that contribute to our skeletal form have been studied extensively in paleoanthropology. With the exception of standing height, examining the genetic basis for differential and specific growth of individual bones and their evolution has been challenging because of limited sample sizes.

RATIONALE

One approach to studying skeletal form is to obtain a map of regions in the genome that affect skeletal development and morphology. Previously, this has been examined mainly through animal models and comparative genomics, but these approaches are largely low throughput. A complementary approach is to examine the genetic basis of variation in skeletal traits in humans. In this work, we applied deep-learning models to 31,221 full-body dual-energy x-ray absorptiometry (DXA) images from the UK Biobank to extract 23 different image-derived phenotypes that include all long-bone lengths and hip and shoulder widths, which we analyzed while controlling for height.

RESULTS

All skeletal proportions (SPs) are highly heritable (~30 to 50%), and genome-wide association studies of these traits identified 145 independent loci. These loci are enriched in genes that regulate skeletal development as well as those that are associated with rare human skeletal diseases and abnormal mouse skeletal phenotypes. Genetic correlation and genomic structural equation modeling indicated that limb proportions exhibited strong genetic sharing but were genetically independent of width and torso proportions. Phenotypic and polygenic risk score analyses identified specific associations between osteoarthritis of the hip and knee, which are the leading causes of adult disability in the United States, and SPs of the corresponding regions. We also found genomic evidence of evolutionary change in arm-to-leg and hip-width proportions in humans, consistent with notable anatomical changes in these SPs in the hominin fossil record. In contrast to cardiovascular, autoimmune, metabolic, and other categories of traits, loci associated with these SPs are significantly enriched both in human accelerated regions and in regulatory elements of genes that are differentially expressed in humans and the great apes throughout development.

CONCLUSION

Our work validates the use of deep-learning models on DXA images to identify specific genetic variants that affect the human skeletal form. It also ties a major evolutionary facet of human anatomical change to pathogenesis."

Short arms and lanky legs: the genetic basis of walking on two legs

The genetic architecture and evolution of the human skeletal form (open access)

The genetic basis, evolution, and health consequences of human skeletal traits.